Infections with viruses, and rhinoviruses in particular, are major causes of asthma exacerbations, and account for a large percentage of the morbidity and economic costs associated with asthma. Current asthma treatment, although effective in the control of allergic asthma, is not always capable of preventing exacerbations of wheezing due to respiratory infections. Based on this unmet clinical need, we propose a program of multifaceted and highly interactive studies to establish the mechanisms by which RV cause exacerbations of asthma. The severity of viral infections and their effects on the lower airway are dependent on factors related to the virus and the host. Our overall hypothesis is that the severity of RV infections and resulting airway dysfunction is critically dependent on a) the interplay between RV replication in the epithelial cell and early innate antiviral responses, and b) variations in the host regulation of proinflammatory and antiviral responses to infection. Our previous work has focused primarily on the ability of RV to infect the lower airway, upregulate inflammation and thereby initiate lower airway obstruction and symptoms. The differential nature of these responses may well determine why certain individuals have significant exacerbations of asthma with virus infections, while others simply have clinical "colds." We now propose five interactive and innovative projects that involve mechanistic studies in isolated populations of cells, and in vivo models in both the human and the mouse. The in vitro projects include experiments to define virus-induced mechanisms of macrophage priming (Project by Bertics), recruitment and activation of neutrophils into the airway (Project by Huttenlocher), and the destruction of epithelial cell nuclear pores to divert cellular metabolism towards viral protein synthesis and replication (Project by Palmenberg). These in vitro studies are complemented by two in vivo models: a genetics study to identify associations with clinical and biologic outcomes of experimentally-induced RV infection (Project by Gern), and a murine model of picornavirus (mengovirus) infection to evaluate mechanisms of virus-induced cellular inflammation. These projects'approach to identify critical host/virus interactions that determine the severity of illness and respiratory dysfunction are synergistic, interactive, and take advantage of a unique set of resources and decades of published experience in this area found at the University of Wisconsin. Collectively, these will studies address clinically relevant gaps in our current understanding of virus-induced airway dysfunction and facilitate the development of new and more efficacious therapeutic strategies. Lay Summary: Infections with rhinovirus, a common cold virus, are the major cause of asthma exacerbations in children, and continue to be a problem for adults with asthma. The goal of this project is to determine why this is so, and identify new approaches to either prevent or treat rhinovirus-induced asthma.